It is now clear that all phases of the myelination program in the CNS and PNS require the complex interplay between adhesion molecules that are expressed in precise temporal sequence and spatial loci. Over the last several years, gene superfamilies of adhesion molecules have been recognized that are essential for nervous system development. These are the immunoglobulin (IgCAM), cadherin, and integrin superfamilies. The multitude of adhesive interactions that are the result of the co-expression of diverse adhesion molecules on the same cell surface make a complete understanding of the adhesion mechanisms that are operative in the nervous system a challenging task. We are a group of four well-established senior investigators, who along with our junior collaborators propose to study the molecular mechanisms underlying membrane adhesion events that are operative during the early phases of myelinogenesis. Thus, we will focus our attention on the functional ablation, through gene knockout technology, of two candidate adhesion moieties of the IgCAM family: the myelin associated glycoprotein and the myelin oligodendrocyte glycoprotein (Project I ). In other work, we will examine athe functional roles played by certain cadherins (Project II) and integrins (Project IV) in the implementation of the myelination program. Lastly, we will study the mechanisms of glial cell migration within nervous tissue (Project II), and, using reagents generated in the other Projects, we eventually expect to tackle the molecular basis for glial cell migration. For all the work that we propose, we will utilize Core facilities: Laboratory Animal, and Gene Assessment. The Core facilities are integral to the Program Project, and when operational will enable us to make rapid progress on each of our collective Aims.